Agents that reverse UV-Induced immune suppression and photocarcinogenesis affect DNA repair
Open accessAbstract
UV exposure induces skin cancer, in part, by inducing immune suppression. Repairing DNA damage, neutralizing the activity of cis-urocanic acid, and reversing oxidative stress abrogate UV-induced immune suppression and skin cancer induction, suggesting that DNA, UCA, and lipid photo-oxidation serve as UV photoreceptors. What is not clear is whether signaling through each of these different photoreceptors activates independent pathways to induce biological effects or whether there is a common checkpoint where these pathways converge. Here, we show that agents known to reverse photocarcinogenesis and photoimmune suppression, such as platelet-activating factor (PAF) and serotonin (5-HT) receptor antagonists, regulate DNA repair. Pyrimidine dimer repair was accelerated in UV-irradiated mice injected with PAF and 5-HT receptor antagonists. Nucleotide excision repair (NER), as measured by unscheduled DNA synthesis, was accelerated by PAF and 5-HT receptor antagonists. Injecting PAF and 5-HT receptor antagonists into UV-irradiated Xeroderma pigmentosum complementation group A-deficient mice, which lack the enzymes responsible for NER, did not accelerate photoproduct repair. Similarly, UV-induced formation of 8-oxo-deoxyguanosine was reduced by PAF and 5-HT receptor antagonists. We conclude that PAF and 5-HT receptor antagonists accelerate DNA repair caused by UV radiation, which prevents immune suppression and interferes with photocarcinogenesis.
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The cis-UCA induced by UV radiation stimulates the production of reactive oxygen species in keratinocytes, which leads to oxidative DNA damage and downstream immunosuppression.
“The cis-UCA induced by UV radiation stimulates the production of reactive oxygen species in keratinocytes, which leads to oxidative DNA damage and downstream immunosuppression [59].”
From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [59]
The Results report that cis-UCA induced reactive oxygen species in keratinocytes, and the Discussion reports oxidative DNA damage marked by 8-oxo-dG. The Discussion describes the resulting immune suppression as a suggested pathway, not an established consequence of that damage; the claim states the full causal chain as fact. Page numbers were not available in our copy. (LLM, conf=0.88)
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Cites
Beissert, S., Rühlemann, D., Mohammad, T., Grabbe, S., El-Ghorr, A., Norval, M., Morrison, H., Granstein, R. D., & Schwarz, T. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.11.6232 · Cited by 77 · cited 3× · see citing works
“Neutralizing the activity of cis-UCA in vivo blocks photocarcinogenesis (Beissert et al., 2001).”
Nishigori, C., Yarosh, D., O’Connor, A., K. Shreedhar, V., Ullrich, S. E., Cox, P., & Kripke, M. L. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.6.2684 · Cited by 22 · cited 2× · see citing works
“However, it is equally important to remember that other types of DNA damage, particularly double strand breaks will also induce immunosuppression and the production of immune suppressive cytokines in vivo (Nishigori et al., 1998; O’Connor et al., 1996).”
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Research works printed but not linked: 45
- Aponte M Jiang W Lakkis M Li MJ Edwards D Albitar L 2008 Activation of platelet-activating factor receptor and pleiotropic effects on tyrosine phospho-EGFR/Src/FAK/paxillin in ovarian cancer Cancer Res 68 5839 5848 18632638 PMC2586603
- Applegate LA Ley RD Alcalay J Kripke ML 1989 Identification of the molecular target for the suppression of contact hypersensitivity by ultraviolet radiation J Exp Med 170 1117 1131 2529340 PMC2189477
- Barber LA Spandau DF Rathman SC Murphy RC Johnson CA Kelley SW 1998 Expression of the platelet-activating factor receptor results in enhanced ultraviolet B radiation-induced apoptosis in a human epidermal cell line J Biol Chem 273 18891 18897 9668065
- Beneke R Geisen C Zevnik B Bauch T Muller WU Kupper JH 2000 DNA excision repair and DNA damage-induced apoptosis are linked to Poly(ADP-ribosyl)ation but have different requirements for p53 Mol Cell Biol 20 6695 6703 10958667 PMC86180
- Benjamin CL Ullrich SE Kripke ML Ananthaswamy HN 2008 p53 tumor suppressor gene: a critical molecular target for UV induction and prevention of skin cancer Photochem Photobiol 84 55 62 18173701
- Bertram C Hass R 2008 Cellular responses to reactive oxygen species-induced DNA damage and aging Biol Chem 389 211 220 18208352
- Black HS deGruijl FR Forbes PD Cleaver JE Ananthaswamy HN deFabo EC 1997 Photocarcinogenesis: an overview J Photochem Photobiol B 40 29 47 9301042
- Boring CC Squires TS Tong T 1992 Cancer Statistics CA Cancer J Clin 42 19 38 1728335
- Breard M Sari MA Frapart Y Boucher JL Ducrocq C Grillon C 2007 The endogenous neurotransmitter, serotonin, modifies neuronal nitric oxide synthase activities Free Radic Res 41 413 423 17454123
- Brubacher JL Bols NC 2001 Chemically de-acetylated 2′,7′-dichlorodihydrofluorescein diacetate as a probe of respiratory burst activity in mononuclear phagocytes J Immunol Methods 251 81 91 11292484
- Bussolati B Mariano F Cignetti A Guarini A Cambi V Foa R 1998 Platelet-activating factor synthesized by IL-12-stimulated polymorphonuclear neutrophils and NK cells mediates chemotaxis J Immunol 161 1493 1500 9686616
- De Fabo EC Noonan FP 1983 Mechanism of immune suppression by ultraviolet irradiation in vivo. I. Evidence for the existence of a unique photoreceptor in skin and its role in photoimmunology J Exp Med 157 84 98 6223114 PMC2187071
- Denizot Y De Armas R Caire F Pommepuy I Truffinet V Labrousse F 2006 Platelet-activating factor and human meningiomas Neuropathol Appl Neurobiol 32 674 678 17083481
- Denizot Y Donnard M Guglielmi L Faucher JL Jaccard A Bordessoule D 2004 Detection of functional platelet-activating factor receptors on leukemic B cells of chronic lymphocytic leukemic patients Leuk Lymphoma 45 515 518 15160913
- Devary Y Rosette C DiDonato JA Karin M 1993 NF-κB activation by ultraviolet light is not dependent on a nuclear signal Science 261 1442 1445 8367725
- El-Ghorr AA Norval M 1995 A monoclonal antibody to cis-urocanic acid prevents the UV-induced changes in Langerhans cells and DTH responses in mice, although not preventing dendritic cell accumulation in lymph nodes draining the site of irradiation and contact hypersensitivity responses J Invest Dermatol 105 264 268 7636311
- Fisher MS Kripke ML 1982 Suppressor T lymphocytes control the development of primary skin cancers in ultraviolet-irradiated mice Science 216 1133 1134 6210958
- Hanawalt PC 2001 Controlling the efficiency of excision repair Mutat Res 485 3 13 11341989
- Hanawalt PC Ford JM Lloyd DR 2003 Functional characterization of global genomic DNA repair and its implications for cancer Mutat Res 544 107 114 14644313
- Kripke ML Cox PA Alas LG Yarosh DB 1992 Pyrimidine dimers in DNA initiate systemic immunosuppression in UV-irradiated mice Proc Natl Acad Sci U S A 89 7516 7520 1502162 PMC49741
- Langie SAS Knaapen AM Houben JMJ van Kempen FC de Hoon JPJ Gottschalk RWH Godschalk RWL van Schooten FJ 2007 The role of glutathione in the regulation of nucleotide excision repair during oxidative stress Toxicol Lett 168 302 309 17207589
- Le Page F Margot A Grollman AP Sarasin A Gentil A 1995 Mutagenicity of a unique 8-oxoguanine in a human Ha-ras sequence in mammalian cells Carcinogenesis 16 2779 2784 7586199
- Melnikova VO Mourad-Zeidan AA Lev DC Bar-Eli M 2006 Platelet-activating factor mediates MMP-2 expression and activation via phosphorylation of cAMP-response element-binding protein and contributes to melanoma metastasis J Biol Chem 281 2911 2922 16306050
- Montrucchio G Sapino A Bussolati B Ghisolfi G Rizea-Savu S Silvestro L 1998 Potential angiogenic role of platelet-activating factor in human breast cancer Am J Pathol 153 1589 1596 9811351 PMC1853395
- Moodycliffe AM Bucana CD Kripke ML Norval M Ullrich SE 1996 Differential effects of a monoclonal antibody to cis-urocanic acid on the suppression of delayed and contact hypersensitivity following ultraviolet irradiation J Immunol 157 2891 2899 8816394
- Nakagawa A Kobayashi N Muramatsu T Yamashina Y Shirai T Hashimoto MW 1998 Three-dimensional visualization of ultraviolet-induced DNA damage and its repair in human cell nuclei J Invest Dermatol 110 143 148 9457909
- Nakane H Takeuchi S Yuba S Saijo M Nakatsu Y Murai H 1995 High incidence of ultraviolet-B- or chemical-carcinogen induced skin tumors in mice lacking the xeroderma pigmentosum group gene Nature 377 165 168 7675085
- Nghiem DX Walterscheid JP Kazimi N Ullrich SE 2002 Ultraviolet radiation-induced immunosuppression of delayed-type hypersensitivity in mice Methods 28 25 33 12231185
- Nishigori C Yarosh DB Ullrich SE Vink AA Bucana CD Roza L 1996 Evidence that DNA damage triggers interleukin 10 cytokine production in UV-irradiated murine keratinocytes Proc Natl Acad Sci U S A 93 10354 10359 8816804 PMC38388
- O’Connor A Nishigori C Yarosh D Alas L Kibitel J Burley L 1996 DNA double strand breaks in epidermal cells cause immune suppression in vivo and cytokine production in vitro J Immunol 157 271 278 8683125
- Pei Y Barber LA Murphy RC Johnson CA Kelley SW Dy LC 1998 Activation of the epidermal platelet-activating factor receptor results in cytokine and cyclooxygenase-2 biosynthesis J Immunol 161 1954 1961 9712066
- Rivas JM Ullrich SE 1992 Systemic suppression of delayed-type hypersensitivity by supernatants from UV-irradiated keratinocytes. An essential role for keratinocyte-derived IL-10 J Immunol 149 3865 3871 1460278
- Schmitt DA Owen-Schaub L Ullrich SE 1995 Effect of IL-12 on immune suppression and suppressor cell induction by ultraviolet radiation J Immunol 154 5114 5120 7730617
- Schwarz A Maeda A Kernebeck K van Steeg H Beissert S Schwarz T 2005 Prevention of UV radiation-induced immunosuppression by IL-12 is dependent on DNA repair J Exp Med 201 173 179 15657287 PMC2212783
- Schwarz A Stander S Berneburg M Bohm M Kulms D van Steeg H 2002 Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair Nat Cell Biol 4 26 31 11780128
- Shen L Ji HF 2008 Theoretical investigation of the photosensitization mechanisms of urocanic acid J Photochem Photobiol B 91 96 98 18359241
- Simon MM Aragane Y Schwarz A Luger TA Schwarz T 1994 UVB light induces a nuclear factor κB (NFκB) activity independently from chromosomal DNA damage in cell-free cytosolic extracts J Invest Dermatol 102 422 427 8151120
- Sreevidya CS Khaskhely NM Fukunaga A Khaskina P Ullrich SE 2008 Inhibition of photocarcinogenesis by platelet-activating factor or serotonin receptor antagonists Cancer Res 68 3978 3984 18483284 PMC2394717
- van Steeg H Kraemer KH 1999 Xeroderma pigmentosum and the role of UV-induced DNA damage in skin cancer Mol Med Today 5 86 94 10200950
- Vink AA Moodycliffe AM Shreedhar V Ullrich SE Roza L Yarosh DB 1997 The inhibition of antigen-presenting activity of dendritic cells resulting from UV irradiation of murine skin is restored by in vitro photorepair of cyclobutane pyrimidine dimers Proc Natl Acad Sci U S A 94 5255 5260 9144224 PMC24665
- Walterscheid JP Nghiem DX Kazimi N Nutt LK McConkey DJ Norval M 2006 Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2A receptor Proc Natl Acad Sci U S A 103 17420 17425 17085585 PMC1859944
- Walterscheid JP Ullrich SE Nghiem DX 2002 Platelet-activating factor, a molecular sensor for cellular damage, activates systemic immune suppression J Exp Med 195 171 179 11805144 PMC2193612
- Wiseman H Halliwell B 1996 Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer Biochem J 313 17 29 8546679 PMC1216878
- Yarosh DB Pena AV Nay SL Canning MT Brown DA 2005 Calcineurin inhibitors decrease DNA repair and apoptosis in human keratinocytes following ultraviolet B irradiation J Invest Dermatol 125 1020 1025 16297204
- Yoshikawa T Rae V Bruins-Slot W Van den Berg JW Taylor JR Streilein JW 1990 Susceptibility to effects of UVB radiation on induction of contact hypersensitivity as a risk factor for skin cancer in humans J Invest Dermatol 95 530 536 2230216
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- Authors
- Sreevidya, C. S., Fukunaga, A., Khaskhely, N. M., Masaki, T., Ono, R., Nishigori, C., & Ullrich, S. E.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Kobe University (JP)
- Corresponding author
- Ullrich, Stephen E.
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2010-05
- Volume
- 130
- Issue
- 5
- Pages
- 1428-1437
- ISSN
- 0022-202X (ISSN-L)
- PMC
- PMC2855396
- OpenAlex
- W2011344575
- Cited by
- 92
- References
- 2
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2020: 7 · 2019: 2 · 2018: 6 · 2017: 7 · 2016: 9 · 2015: 5 · 2014: 3 · 2013: 8 · 2012: 13
- FWCI
- 13.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA112660, CA131207, CA16672, T32-CA-09598-15)
- Topics
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Epidemiology › Nonmelanoma Skin Cancer Studies
- Keywords
- photocarcinogenesis, DNA repair, platelet-activating factor, serotonin antagonists, pyrimidine dimer repair, nucleotide excision repair, xeroderma pigmentosum, 8-hydroxy-2'-deoxyguanosine, cis-urocanic acid, skin cancer prevention
- MeSH terms
- 8-Hydroxy-2'-Deoxyguanosine, Animals, Deoxyguanosine, DNA Repair, Immune Tolerance, Mice, Inbred C57BL, Mice, Mutant Strains, Piperazines, Platelet Activating Factor, Serotonin Antagonists, Skin Neoplasms, Ultraviolet Rays, Urocanic Acid, Xeroderma Pigmentosum, Reactive Oxygen Species, Oxidative Stress, Mice, Xeroderma Pigmentosum Group A Protein
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